This K23 proposal on the role of leptin in neuroendocrine function and the treatment of HA combines a rigorous research agenda, close personal mentoring, and coursework tailored to train Dr. Jean L. Chan as an independent clinical investigator. Dr. Chan is currently a third-year fellow in Endocrinology and Metabolism who has an interest in human leptin physiology and treatment studies and has recently completed the first interventional study to evaluate the role of leptin in the neuroendocrine and immune response to fasting in healthy lean men - a subject of profound physiologic interest with substantial clinical relevance and significance for both high-leptin and low-leptin states. She is also currently enrolled at Harvard Medical School in the Clinical Scholar's program designed to train postdoctoral fellows in clinical investigation. For the K23 proposal, she intends to evaluate whether a threshold level of leptin is of importance in the neuroendocrine response to fasting by studying obese leptin-resistant men and whether gender has an effect on this response by studying women, who have different leptin physiology from men. The study design will involve double-blind, randomized, placebo-controlled fasting studies with leptin administration. This research may elucidate the compensatory neuroendocrine mechanisms responsible for the plateauing effect of caloric restriction in the treatment of obesity and contribute to our understanding of the neuroendocrine abnormalities associated with eating disorders. This proposal will also evaluate leptin as a potential treatment to restore menstrual cycles in women with HA, a low-leptin state associated with abnormalities in GnRH pulsatility as well as other neuroendocrine axes and bone metabolism. Dr. Chan is currently conducting a pilot study to evaluate the feasibility of this hypothesis and will use a larger, placebo-controlled study design with leptin administration for the K23 proposal. Dr. Christos Mantzoros, an established expert and leader in the leptin field, will be Dr. Chan's mentor. The Clinical Scholars program will encompass a thesis-level research effort, and Dr. Chan has assembled a thesis committee who is monitoring and guiding her progress. She will also have the opportunity to take advanced biostatistics classes at Harvard Public Health School. The proposed research will not only provide critically important and novel scientific information in the area of leptin physiology in humans but it will serve as the foundation for developing new avenues of future research.